Aspirin Effects and Endothelial Regulation of Vascular Smooth Muscle in Hypertension. Arachidonic metabolites, prostacyclins and prostaglandins synthesized via the enzyme cyclooxygenase are important paracrine products of endothelium in heart and large blood vessels. Endothelium also produces other vasoactive substances such as endothelins and nitric oxide (NC). Hypertension, atherosclerosis, and aging have been reported to accompany endothelial dysfunctions. Inhibition of cyclooxygenase with Acetylsalicylic acid (aspirin, ASA) in platelets which are the source of thromboxane A2, has been successful in controlling the development of pregnancy induced hypertension (PIH). Aspirin is also widely prescribed to manage vascular occlusive disorders in man. Recently, aspirin was reported to suppress the immune system in humans. Additionally, immunosuppressive drugs such as Cyclosporin A (CsA) and Rapamycin prescribed for organ transplant patients are known to alter the endothelial function in blood vessels. Aspirin in vitro is reported to bring about conformational changes in plasma membrane proteins in blood cells and is known to alter the alpha2-adrenoceptors in platelets. We have shown that a 10 week ASA treatment of female SHR rats enhanced the aortic ring contractility in response to alpha-adrenoceptor stimulation without any appreciable decrease in blood pressure. Also, aortic rings from male SHR rats with and without endothelium in the presence of o.2 mM ASA have shown enhanced sensitivity to alpha-adrenoceptor stimulation. These results indicate that ASA may be able to reverse to some extent the permeability defect of plasma membranes associated with hypertensive disease. The purpose of this study is to test the hypothesis that ASA induced changes in conformation and dynamics of plasma membrane proteins in VSM- improve Ca2+ transport, enhance the tone and may affect the development of genetic hypertension in SHR rats. Accordingly, the specific aims of this study are to; 1) Evaluate the effects of varying doses of ASA (Aspirin) by monitoring the blood pressure during the development of hypertension in SHR rats. (2) Evaluate the effects of different concentrations of ASA (Aspirin), Indomethacin, CsA, and Rapamycin both in vitro and in vivo on the regulation of VSM tone from SHR and WKY rats. 3) Investigate in vitro the effects of ASA (Aspirin), CsA, Indomethacin and Rapamycin on reactivity of aortic rings from SHR as well as WKY rats with and without the paracrine mediation of endothelium. The extracellular and intracellular Ca2+ pools will be exploited selectively. The active tension generated will be measured in response to each Ca2+ pool and athe mechanisms of Ca2+ conductance will be evaluated in athe presence of ASA, Indomethacin, CsA and Rapamycin in aortic rings with and without intact endothelium. This will enable us to identify the Ca2= conductance mechanisms which are influenced by in vivo and/or in vitro ASA treatment.